Tissue-based validation of COPD Genetic Studies using Lung Health Study Cohort Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in North America, affecting 10-12 million Americans. Although cigarette smoking is the most common environmental risk factor involved in development of COPD, only 10-20% of heavy smokers ever develop symptomatic disease. Evidence from both animal and human studies provides support for genetic determinants for disease risk and progression, yet only a small proportion of the potential causal genes have been identified. Genome wide association studies are powerful analytic tools that can identify genetic variants that contribute to disease development and progression. Only recently have these tools been used to characterize complex lung diseases such as COPD. As part of the (U01HG004738-01) Genome Wide Association Study of Chronic Obstructive Pulmonary Disease;Barnes PI) we will complete high-throughput genotyping which includes >550,000 SNPs representing all known genes on 4,287 European American participants of the multi-center NHLBI-funded Lung Health Study (LHS). For the current application, we propose a broad, tissue-based validation approach utilizing genomics and protein detection strategies. In Specific Aim 1, we will validate the most significant associations between SNPs in genes associated with rate of decline of lung function and COPD susceptibility by evaluating genome-wide gene expression data in COPD lung tissue specimens from the LTRC (samples from patients with COPD (N=30) and non-COPD (control) smokers with normal lung function (N=11) using the Illumina" Sentrix HumanRef-8 Expression BeadChip (Illumina, San Diego, CA). In Specific Aim 2, further validation of genetic associations will incorporate the protein based strategies of immunoblotting and immunohistochemistry focusing on dysregulated expression and in situ localization in COPD tissue compared with control specimens. Our studies will provide proof-of-principle support for the use of tissue-based validation strategies for GWAS-defined candidate genes. In addition to critical validation of the salient findings of our COPD GWAS under a separate funding mechanism, added value to this application includes the extensive profiling of 40+ LTRC samples that will be readily available to the scientific community to advance other studies of obstructive lung disease. (End of Abstract) PUBLIC HEALTH RELEVANCE: COPD is a significant public health concern, and a better understanding of the pathogenic nature of this pervasive condition is critical to finding novel therapies. We anticipate correlating our genetic variants identified in the LHS genetic studies with gene expression data obtained from lung tissue of well-characterized COPD subjects of varying disease severity obtained from the LTRC in order to identify and validate novel candidate genes involved in the pathogenesis of COPD. In addition, the proposed studies will provide proof-of-principle support for the value of complementary RNA and protein-based approaches in the validation of genetic results for complex lung disorders and added value to this application includes the extensive profiling of 40 LTRC lung tissue samples that will be readily available to the scientific community to advance other studies of obstructive lung disease.